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US8771643B2 - Use of analgesic potentiating compounds to potentiate the analgesic properties of an analgesic compound - Google Patents

Use of analgesic potentiating compounds to potentiate the analgesic properties of an analgesic compound Download PDF

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US8771643B2
US8771643B2 US12/811,528 US81152809A US8771643B2 US 8771643 B2 US8771643 B2 US 8771643B2 US 81152809 A US81152809 A US 81152809A US 8771643 B2 US8771643 B2 US 8771643B2
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ibuprofen
analgesic
isomer
pharmaceutically acceptable
acceptable salt
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US20110014127A1 (en
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Bernard P. Schachtel
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SCHACHTEL RESEARCH COMPANY Inc
SRC Inc
Schabar Research Associates LLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect

Definitions

  • analgesic potentiation is a type of pharmacologic activity that occurs when greater analgesic effectiveness is measured in patients treated with an analgesic drug combined with a non-analgesic ingredient than in patients treated with the analgesic drug alone. There are many reasons for the potentiation of an analgesic.
  • analgesic effectiveness it would be desirable to enhance the clinical outcome for the patient (i.e., analgesic effectiveness). It would also be desirable to reduce the dosage of the analgesic (i.e., “optimal dose”) that is administered in view of possible side effects exhibited by the same or higher dose of the analgesic (i.e., “optimal analgesia,” a reduction of the risk:benefit ratio). It would also be desirable to provide greater pain relief or faster onset of pain relief. It would also be desirable to provide a longer duration, which results in less frequent dosing and better compliance. Finally, if the analgesic can improve one or more qualities of pain or one or more bodily functions of the patient or provide definite improvement of the patient, which will be discussed in greater detail below, these would be added benefits.
  • the measurement instruments for these overall effects are standard methods for determining general patient response such as analgesic activity.
  • analgesic potentiation for example, clinical investigators by convention utilize these methods to demonstrate, to a statistically significant degree, that a combination of drugs provides “greater reduction in pain intensity” and “more pain relief” than the single-ingredient analgesic.
  • conventional methods may not be able to demonstrate that a combination of the analgesic with another drug provides analgesic effectiveness to a greater extent than the analgesic alone.
  • compositions comprising an analgesic and a sufficient amount of an antihistamine to enhance the analgesic properties of the analgesic.
  • the methods described herein are useful for evaluating qualities of pain, definite improvement, and one or more bodily functions of a subject afflicted with pain.
  • the compositions described herein are useful in improving the quality of pain in a subject or a bodily function of a subject afflicted with pain or definite improvement of a subject afflicted with pain.
  • FIG. 1 shows the reduction in throat soreness over 6 hours of several analgesics (acetaminophen 500 mg (APAP), ibuprofen 200 mg, celecoxib 200 mg, naproxen sodium 220 mg) and placebo.
  • APAP acetaminophen 500 mg
  • ibuprofen 200 mg ibuprofen 200 mg
  • celecoxib 200 mg ibuprofen 200 mg
  • naproxen sodium 220 mg placebo.
  • FIG. 2 shows the reduction in throat soreness over 6 hours of ibuprofen 200 mg (Ibu) and several ibuprofen combinations (ibuprofen 200 mg+loratadine 20 mg (Ibu+Loratadine), ibuprofen 200 mg+hydroxyzine 50 mg (Ibu+Hydroxyzine), ibuprofen 200 mg+nizatidine 150 mg (Ibu+Nizatidine).
  • FIG. 3 shows the reduction in throat soreness at time points over 6 hours of ibuprofen 200 mg and placebo.
  • FIG. 4 shows the percentage of patients who achieved their own Definite Improvement Level on the Throat Soreness Scale of several analgesics and placebo.
  • FIG. 5 shows the reduction in difficulty swallowing over 6 hours of ibuprofen combinations and ibuprofen 200 mg.
  • FIG. 6 shows the reduction in difficulty talking over 6 hours of several analgesics and placebo.
  • FIG. 7 shows the reduction in difficulty talking over 6 hours of ibuprofen combinations and ibuprofen 200 mg.
  • FIG. 8 shows the reduction in throat swelling over 6 hours of ibuprofen combinations and ibuprofen 200 mg.
  • FIG. 9 shows the reduction in throat swelling at time points over 6 hours of ibuprofen 200 mg and placebo.
  • FIG. 10 shows the reduction in the Quality-of-Pain Index over 6 hours of ibuprofen combinations and ibuprofen 200 mg.
  • FIG. 11 shows the reduction in the Annoying Quality-of-Pain Scale over 6 hours of several analgesics and placebo.
  • “Optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.
  • the phrase “optionally substituted lower alkyl” means that the lower alkyl group can or cannot be substituted and that the description includes both unsubstituted lower alkyl and lower alkyl where there is substitution.
  • the term “comparative agent” as used herein is any agent that is used to compare or evaluate the ability of an antihistamine to potentiate the analgesic properties of an analgesic.
  • the comparative agent can be a placebo, another drug, or a combination of drugs.
  • the effects of a known analgesic can be evaluated and compared to that of the comparative agent, confirming the pharmacologic activity of the analgesic and thus validating the method itself.
  • the comparative agent is the administration of just the analgesic to the patient.
  • the effects of the antihistamine on the analgesic can be evaluated and compared to that of the analgesic alone, thus identifying any additional pharmacologic activity provided by the antihistamine (“analgesic potentiation”).
  • the method includes:
  • a method for evaluating definite improvement of a subject afflicted with one or more adverse symptoms after the administration of one or more drugs to the subject includes:
  • the methods described herein are more sensitive with respect to detecting and measuring a patient's response to one or more drugs.
  • the methods can be used in a variety of therapeutic areas exhibiting adverse symptoms including, but not limited to, gastrointestinal (e.g., for patients with heartburn, abdominal pain, nausea and vomiting); respiratory (e.g., for patients with asthma, chronic obstructive lung disease, cough, nasal congestion); musculoskeletal (e.g., for patients with osteoarthritis, sprains, rheumatoid arthritis, spinal disorders); dermatological (e.g., for patients with eczema, hives, psoriasis, sun sensitivity); psychiatric (e.g., for patients with depression, anxiety, sleep disorders); CNS (e.g., for patients with tension headache, migraine headache, light sensitivity); and allergic disorders (e.g., for patients with seasonal allergic rhinitis, perennial allergic rhinitis).
  • gastrointestinal e.g., for patients with
  • the methods described herein measure a definite improvement after the administration of the drug(s).
  • definite improvement is defined herein as the ability of the drug to elicit a response followed by subsequent questioning to evaluate whether or not the subject's condition has improved.
  • “definite improvement” can be evaluated by directly asking the subject certain questions that will prompt the subject to precisely consider whether or not the subject's condition has unequivocally improved such that the response is significantly perceptible to the subject and is so reported by the subject.
  • the degree or amount of the response can be measured using a multipoint scale, which can vary from little to no improvement to certain improvement. “Definite improvement” is greater than 50% improvement to 100% improvement as perceived and reported by the patient on this scale.
  • “definite improvement” is at or lower than a response level perceived by the subject on one or more individual rating scales.
  • patients with asthma may be able to report “definite improvement” because several symptoms have, in subtle ways, improved, or these patients may be able to report less chest tightness, a sensory quality of asthma, even though, in clinical trials, they may not report “relief” of asthma symptoms.
  • Patients with osteoarthritis may report less joint “stiffness,” a sensory quality of arthritic status, even though they may not report “relief” of their disease in clinical studies.
  • Patients with hives may report an ability to move an effected body part more freely (i.e., function) even though they may not report “relief” of their condition in research trials.
  • specific “patient-oriented” endpoints may reveal the actual clinical benefits.
  • Each specific endpoint of patient dis-ease (rather than physician-diagnosed disease) may reveal the actual clinical benefit to the patient.
  • Examples of definite improvement associated with pain include, but are not limited to, headache, backache, sinusitis, earache, cough discomfort, sinus pain associated with nasal congestion, difficulty breathing, toothache, sprained ankle, muscle strain, sprained or torn ligaments, and bursitis.
  • the methods described herein are useful in evaluating if a drug (alone or in combination with other drugs) is useful in eliciting a desirable response.
  • a drug alone or in combination with other drugs
  • the response elicited by the patient when administered a drug can be compared to the patient's response when the subject is administered a comparative agent as defined above.
  • described herein is a method for evaluating one or more qualities of pain in a subject afflicted with pain, comprising:
  • a method for evaluating one or more bodily functions of a subject afflicted with pain comprising:
  • a method for evaluating definite improvement of a subject afflicted with pain comprising:
  • the methods described herein use rating scales that measure changes in the words which patients actually use to describe their discomfort and whether or not they achieved definite improvement on each scale, instead of traditional analgesic methods (i.e., measuring differences in overall pain intensity or relief).
  • traditional analgesic methods i.e., measuring differences in overall pain intensity or relief.
  • the methods described herein for evaluating pain in a patient and the effect of the combination of an analgesic and antihistamine utilize non-standard methods:
  • the methods described herein represent a progression beyond conventional analgesic measurement instruments and attempt to measure “patient-oriented” clinical effects in order to determine analgesic potentiation, i.e., if sample antihistamine/analgesic combinations deliver more pronounced analgesia compared to the respective single-ingredient analgesics. Measuring conventional endpoints (e.g., “pain” and “relief”) may obscure the identification of clinical benefits.
  • the type of pain can be acute or chronic.
  • the source of the pain can vary and includes, but is not limited to, renal colic, colic, gallstone pain, ulcer pain, sinus pain, migraine headache, cluster (“histamine”) headache, muscle contraction headache, osteoarthritis, rheumatoid arthritis, gouty arthritis, other arthritides, ligamentous sprain, bursitis, soft tissue injuries (e.g., torn subpatellar meniscus or ligament), skeletal muscle (e.g., low back pain, muscle ache, muscular contusion, muscular strain, muscle spasm, neck spasm/pain, etc.).
  • the source of pain can be post-operative (e.g., following abdominal surgery, thoracic surgery, neurosurgery, orthopedic surgery, podiatric surgery, anorectal surgery, urologic surgery, gynecologic surgery, episiotomy, oral surgery, head and neck surgery, plastic surgery, etc.).
  • post-operative e.g., following abdominal surgery, thoracic surgery, neurosurgery, orthopedic surgery, podiatric surgery, anorectal surgery, urologic surgery, gynecologic surgery, episiotomy, oral surgery, head and neck surgery, plastic surgery, etc.
  • the source of pain can be the result of infection (e.g., a subject experiencing pain as a result of sinusitis, laryngitis, pharyngitis, otitis media, cellulitis, abscess, meningitis, conjunctivitis, osteoarthritis, osteomyelitis, etc.),
  • the source of pain can be the result of vascular insufficiency (e.g., a subject experiencing pain as a result of peripheral vascular disease or coronary artery disease).
  • the source of pain can be the result of a previous treatment (e.g., a subject experiencing pain as a result of receiving chemotherapy or radiation) or the result of cancer (e.g., primary carcinoma or metastatic bone pain).
  • a previous treatment e.g., a subject experiencing pain as a result of receiving chemotherapy or radiation
  • cancer e.g., primary carcinoma or metastatic bone pain
  • the compositions described herein improve one or more qualities of pain in a subject.
  • the phrase “improve the quality of pain” is defined herein as the ability of the composition to reduce the subject's sensation of a particular quality or qualities of pain.
  • the subject may experience a hot, scratchy, raw, raspy, dry, tight, swollen, or burning sensation or consider the sensation annoying or irritating.
  • qualities of pain associated with a sore throat as caused, e.g., by pharyngitis, seasonal allergic rhinitis (“hayfever”), perennial allergic rhinitis).
  • qualities of pain associated with other painful conditions include, but are not limited to, headache, backache, sinusitis, earache, toothache, sprained ankle, joint pain, arthritis, bursitis, vascular insufficiency, cancer-related pain, post-operative pain.
  • compositions described herein improve one or more bodily functions of a subject afflicted with pain.
  • improved one or more bodily functions is defined herein as the ability of the composition to improve a bodily function of a subject that is debilitated or weakened as a result of pain experienced by the subject. For example, when a subject is experiencing a sore throat, the subject may have trouble swallowing or difficulty talking, where swallowing and talking are the bodily functions.
  • bodily functions associated with a sore throat as caused, e.g., by tonsillopharyngitis, oral mucositis).
  • bodily functions associated with other painful conditions include, but are not limited to, headache, backache, sinusitis, earache, toothache, sprained ankle, joint pain, arthritis, bursitis, vascular insufficiency, cancer-related pain, post-operative pain.
  • compositions described herein can be shown directly to provide definite improvement.
  • definite improvement is defined herein as the ability of the composition to reduce the subject's sensation of a particular quality(ies) of pain or bodily function(s) at least to his/her own level defining successful treatment. Grading a reduction in pain intensity may be inadequate to detect improvement in physical status. Rather than infer a change in status by subtracting one “pain” rating from another, as is commonly performed in clinical trials, subjects can define their own criterion of successful treatment as a direct indicator of therapeutic efficacy.
  • one subject with a “swollen” throat may rate it “10” on a 0-10 scale: for him/her, reducing this sensation to “6” or below may be the clear measure of whether or not a medication is “working.”
  • reducing this sensation to “6” or below may be the clear measure of whether or not a medication is “working.”
  • Other examples apply to other qualities of pain or bodily functions.
  • Each patient's “definite improvement level” on a rating scale can be used to identify a successful treatment response, or not.
  • response rates of patients treated with a drug can be compared to those of patients treated with placebo, identifying therapeutic efficacy.
  • the evaluation methods described herein provide numerous advantages over existing techniques. First, it is possible to detect wide differences (e.g., ranging from 20% to over 100%) between some antihistamine/analgesic combinations and the corresponding single-ingredient analgesic. Additionally, the methods are more sensitive with respect to differentiating the effects of different combinations of analgesic and antihistamine. For example, unlike the requirement for an entry level ⁇ 7 for the conventional scale Throat Soreness Scale (TSS), there are no admission criteria for using the methods described herein, which ranged from 0 to 10 at baseline.
  • TSS Throat Soreness Scale
  • the methods described herein were used by the patients in each treatment group to measure impressive effects and identify clear drug-vs.-placebo and between-drug differences. Due to greater sensitivity, the methods described herein may require fewer patients in a clinical trial than with a conventional rating scale and be capable of discerning clinical effects better.
  • the composition for improving. comprises an analgesic and a sufficient amount of an antihistamine to enhance the analgesic properties of the analgesic.
  • analgesic and antihistamine are FDA-approved chemical compounds.
  • the analgesic comprises a non-opioid.
  • non-opioids include, but are not limited to, acetaminophen, aspirin, ibuprofen, naproxen sodium, naproxen, indomethacin, flurbiprofen, ketoprofen, lornoxicam, meloxicam, piroxicam, oxaprozin, etodolac, ketorolac, nabumetone, or other nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), selective COX-2 inhibitors (e.g., celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522, L-745,337, and NS398), NDMA-inhibitors, or any combination thereof, optionally with other components such as, for example, caffeine or other analgesic adjuvant(s), with or without other ingredients for non-anal
  • the analgesic comprises an opioid including, but not limited to, morphine, codeine, buprenorphine, hydrocodone, oxycodone, fentanyl, tramadol, pentazocine, meperidine, or any combination thereof with or without caffeine or other analgesic adjuvant(s), optionally with other ingredients for non-analgesic indications (e.g., “cough-cold products,” which may contain, in varying combinations, an analgesic/antipyretic, an antihistamine, an antitussive, a decongestant, an expectorant, etc.).
  • opioid including, but not limited to, morphine, codeine, buprenorphine, hydrocodone, oxycodone, fentanyl, tramadol, pentazocine, meperidine, or any combination thereof with or without caffeine or other analgesic adjuvant(s), optionally with other ingredients for non-analgesic indications (e.g., “cough
  • suitable pharmaceutically acceptable salts of ibuprofen include ibuprofen lysinate, dexibuprofen lysinate, and sodium and potassium salts of ibuprofen.
  • Other examples of pharmaceutically acceptable salts of ibuprofen include salts with alkaline earth metals, such as magnesium, aluminum, iron, zinc, copper, nickel or cobalt, and amino acid salts, particularly the basic amino acid salts such as lysine or arginine.
  • ibuprofen examples include, but are not limited to racemic and individual purified forms of (S) ibuprofen and (R)-ibuprofen isomers, including (S)-ibuprofen-(S)-lysine, (S)-ibuprofen-(R)-lysine, (R)-ibuprofen-(S)-lysine and (R)-ibuprofen-(R)-lysine and combinations thereof.
  • the antihistamine comprises a sedating H 1 antihistamine, a non-sedating H 1 -antihistamine, a H 2 -antihistamine, an experimental H 3 - and H 4 -receptor antagonist, or any combination thereof.
  • sedating H 1 -antihistamines include, but are not limited to, diphenhydramine, hydroxyzine, any salt or isomer thereof, or a combination thereof.
  • Useful non-sedating H 1 -antihistamines include, but are not limited to, astemizole, azatadine, azelastine, cetirizine, ebastine, fexofenidine, ketotifen, lodoxamide, loratadine, desloratadine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, and terfenadine, any salt or isomer thereof, or any combination thereof.
  • H 2 -antihistamines include, but are not limited to, nizatidine, ranitidine, famotidine, cimetidine, roxatidine, lafutidine, ebrotidine, burimamide, metiamide, tiotidine, oxmetidine, pabutidine, loxtidine, any salt or isomer thereof, or any combination thereof.
  • H 3 -antihistamines include, but are not limited to, A-349,821, ABT-239, ciproxifan, clobenpropit, or thioperamide, any salt or isomer thereof, or any combination thereof.
  • H 4 -antihistamines include, but are not limited to, thioperamide, JNJ 7777120, VUF-6002, any salt or isomer thereof, or any combination thereof.
  • analgesic and antihistamine can vary depending upon the selection of the analgesic and antihistamine, the type of pain experienced by the subject, the route and means of drug administration, and the frequency of dosing.
  • the analgesic is a single dosage from 0.1 mg to 1,500 mg and the antihistamine is a single dosage from 0.1 mg to 1 g.
  • the amount of analgesic is 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1,000 mg, 1,100 mg, 1,200 mg, 1,300 mg, 1,400 mg, or 1,500 mg, where any value can form a lower or upper endpoint of a range.
  • the amount of antihistamine is 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1,000 mg, where any value can form a lower or upper endpoint of a range.
  • the weight ratio of analgesic to antihistamine is 20:1, 18:1, 16:1, 14:1, 12:1, 10:1, 8:1, 6:1, 4:1, 2:1, or 1:1.
  • the analgesic and antihistamine can be formulated into a variety of pharmaceutical compositions.
  • the pharmaceutical compositions can be prepared using techniques known in the art.
  • the composition is prepared by admixing the analgesic and the antihistamine with a pharmaceutically-acceptable carrier.
  • the analgesic and antihistamine are formulated such that the analgesic and the antihistamine are in separate delivery devices.
  • the analgesic and the antihistamine can be administered to the subject separately and independently (e.g., to achieve immediate-release or delayed-release responses by and to one or both component drugs).
  • the antihistamine can be administered first followed by the administration of the analgesic.
  • the nizatidine when the antihistamine is nizatidine and the analgesic is ibuprofen, the nizatidine can be administered first followed by the administration of ibuprofen.
  • the nizatidine when the nizatidine is an immediate-release preparation (e.g., a powder), the dissolution and bioavailability of the nizatidine is increased when compared to the slower dissolution and bioavailability of ibuprofen in a compressed tablet.
  • the analgesic and antihistamine can be formulated in any excipient the subject can tolerate.
  • excipients include, but are not limited to, water, saline, Ringer's solution, dextrose solution, Hank's solution, and other aqueous physiologically balanced salt solutions.
  • Nonaqueous vehicles such as fixed oils, vegetable oils such as olive oil and sesame oil, triglycerides, propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate can also be used.
  • Other useful formulations include suspensions containing viscosity-enhancing agents, such as sodium carboxymethylcellulose, sorbitol, or dextran.
  • the pharmaceutical compositions can include other components that are non-analgesics and non-antihistamines.
  • the pharmaceutical compositions can contain minor amounts of additives, such as substances that enhance isotonicity and chemical stability.
  • buffers include phosphate buffer, bicarbonate buffer and Tris buffer, while examples of preservatives include thimerosol, cresols, formalin and benzyl alcohol.
  • the compounds described herein are admixed with a non-FDA approved delivery device such as, for example, sunscreen or a nutraceutical.
  • the pharmaceutical compositions can also include one or more active ingredients such as antimicrobial agents, antiinflammatory agents, anesthetics, decongestants, antitussives, expectorants, antipyretics, and the like.
  • compositions can be administered in a number of ways.
  • the compositions can be administered orally as a tablet or pill.
  • the analgesic and antihistamine can be formulated with a variety of suitable carriers, excipients, and diluents known in the art. Examples of such materials include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propylhydroxybenzoates, talc, magnesium stearate and mineral oil.
  • the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents.
  • compositions of the invention may be formulated so as to provide quick release, sustained release, or delayed release of the analgesic and/or antihistamine after administration to the subject.
  • Different pharmaceutic formulations and different processing techniques may be employed to alter the pharmacokinetic characteristics of the compositions, including, without limitation, time to maximum concentration, maximum concentration, area under the curve, etc.
  • the analgesic and antihistamine can be formulated with biodegradable polymers such as, for example, polylactide, polyglycolide, or polylactide-co-glycolide, where the analgesic and antihistamine are incorporated in a polymeric matrix.
  • the tablet or pill can be formulated such that the tablet or pill contains two or more layers of varying disintegration and dissolution rates.
  • the compositions can be encapsulated in order to control the rate of release of the analgesic and antihistamine.
  • the analgesic and antihistamine can be formulated into one tablet or pill or, in the alternative, the analgesic and antihistamine can be formulated into separate tablets or capsules.
  • compositions described herein can be administered topically (including ophthalmically, vaginally, rectally, buccally, intranasally).
  • Formulations for topical administration can include ointments, lotions, creams, gels, patches, drops, suppositories, sprays, liquids and powders.
  • the compositions described herein can be prepared as sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles if needed for collateral use of the disclosed compositions and methods, include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
  • Intravenous vehicles if needed for collateral use of the disclosed compositions and methods, include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives can also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.
  • improvement and differences from Baseline may be reported as medians and percentage differences.
  • reaction conditions e.g., component concentrations, desired solvents, solvent mixtures, temperatures, pressures and other reaction ranges and conditions that can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions.
  • a randomized, double-blind, placebo-controlled single-dose study was performed. In order to be eligible for the study, patients were required to have a history of an acute sore throat and physical evidence of pharyngitis. A total of 99 patients who met pre-specified inclusion and exclusion criteria, including moderate to severe throat pain intensity, as measured by a score ⁇ 7 on the Throat Soreness Scale (TSS), were admitted to the study.
  • TSS Throat Soreness Scale
  • each patient was randomly assigned one dose of ibuprofen 200 mg (ibuprofen); ibuprofen 200 mg with hydroxyzine 50 mg (ibuprofen/hydroxyzine); ibuprofen 200 mg with loratadine 20 mg (ibuprofen/loratadine); ibuprofen 200 mg with nizatidine 150 mg (ibuprofen/nizatidine); acetaminophen 500 mg (acetaminophen); acetaminophen 500 mg with ceterizine 20 mg (acetaminophen/ceterizine); celecoxib 200 mg (celecoxib); celecoxib 200 mg with ceterizine 20 mg (celecoxib/ceterizine); naproxen sodium 220 mg (naproxen); naproxen sodium 220 mg with loratadine 20 mg (naproxen/loratadine); or placebo.
  • TSS Throat Soreness Scale
  • SwoTS Swollen Throat Scale
  • DSS Difficulty Swallowing Scale
  • DTS Difficulty Talking Scale
  • TEST PROTOCOL Quality-of-Pain Scale
  • Visit 1 Screening (Pre-Randomization Period)
  • Each patient will provide a medical history including date of birth, duration and assessment of pharyngitis, including other symptoms of upper respiratory tract illness, significant past diseases/procedures and current conditions. All results will be recorded on the appropriate CRFs.
  • Vital signs will be taken in the sitting position, including oral temperature, heart rate, respiratory rate and blood pressure. Screening vital signs should be taken within the 60 minutes prior to administration of the dose of study medication. This information will be recorded.
  • Urine Pregnancy Test There are no laboratory tests other than a Urine Pregnancy Test on eligible female patients. If the patient is a female of childbearing potential, a Urine Pregnancy Test will be performed, reviewed, and confirmed as negative prior to the patient's enrollment in the study. Results of the pregnancy test will be recorded on a Pregnancy Test Log and in the CRF.
  • laboratory tests for patients with pharyngitis e.g., Abbott Quick 1-step Strep Test, throat culture, MonoSpot Test, CBC, etc. may be performed according to standard medical procedures.
  • patients will be dispensed the patient assessment pages from the CRF (i.e., pages containing the rating scales for throat soreness, difficulty swallowing, swollen throat, difficulty talking, etc.) for use while in the unit and will be instructed on their use by the Study Nurse in order to capture all patient assessments directly from the patient.
  • CRF i.e., pages containing the rating scales for throat soreness, difficulty swallowing, swollen throat, difficulty talking, etc.
  • the Study Nurse will review all data recorded by the patient. Data from the patient assessments will be transcribed onto the appropriate Summary Data CRF pages.
  • the Medication Nurse will administer separately the two (2) study medication capsules assigned to the patient. Each patient will be observed to swallow each capsule with a few swallows of water, so that approximately 240 ml of water is consumed. The time of study medication administration and the patient's study medication number will be recorded in the source document and on the appropriate CRF.
  • Visit 1 15 Minutes Up to 2 Hours Post-Dose (Treatment Period)
  • the study site will supply one dose of rescue analgesic medication, acetaminophen 650 mg, for each patient.
  • rescue analgesic medication should be delayed for at least two hours following consumption of the first dose of study medication, if possible. Rescue analgesic medication will be permitted at any time, as the needs of the patient dictate.
  • rescue analgesia The following details concerning rescue analgesia will be collected: date and time taken, drug name and dose regimen. Just prior to taking rescue medication, patients will provide responses to pain assessments.
  • acetaminophen 650 mg the Investigator will provide advice for additional relief medication according to standard medical care. Any additional relief medication will be source documented and transcribed accordingly onto the concomitant medication CRF.
  • Oral temperature will be recorded on the appropriate CRF at the two-hour post-administration of study medication or within +/ ⁇ 5 minutes of receiving rescue medication or withdrawal due to reasons other than rescue medication.
  • the study site will supply one dose of rescue analgesic medication, acetaminophen 650 mg, for each patient.
  • rescue analgesic medication should be delayed for at least two hours following consumption of the first dose of study medication, if possible. Rescue analgesic medication will be permitted at any time, as the needs of the patient dictate.
  • rescue analgesia The following details concerning rescue analgesia will be collected: date and time taken, drug name and dose regimen. Just prior to taking rescue medication, patients will provide responses to pain assessments.
  • acetaminophen 650 mg orally the Investigator will provide advice about additional relief medication according to standard medical care. Any additional relief medication will be source documented and transcribed accordingly onto the concomitant medication CRF.
  • the patient assessment pages of the CRF used during the patient's 2-hour evaluation in the unit will be collected and reviewed by the Study Nurse while the patient is still at the site. Data from the patient assessments will be transcribed onto the appropriate Summary Data CRF pages.
  • the patient will be discharged from the unit with a Diary.
  • the Study Nurse will instruct the patient how to use the Diary on an hourly basis, filling out the following procedures at 3, 4, 5, and 6 hours:
  • the Study Nurse will instruct the patient how to use the Diary by filling out the 10 Quality-of-Pain Scales after the other patient assessments are completed at 6 hours.
  • the patient will also be instructed to document any use of rescue medication and any adverse events that may occur
  • the Study Nurse will also instruct the patient about study conditions through 6 hours:
  • the patient will return to the study site for the Follow-up Visit ⁇ 5 days post administration of study medication with his/her patient assessment diary. The following procedures will be performed:
  • Patients will be dispensed the patient assessment pages from the CRF (i.e., pages containing the Baseline rating scales for throat soreness, difficulty swallowing, swollen throat, difficulty talking, etc.) and will be instructed on their use by the Study Nurse in order to capture all patient assessments directly from the patient.
  • CRF i.e., pages containing the Baseline rating scales for throat soreness, difficulty swallowing, swollen throat, difficulty talking, etc.
  • the Study Nurse will review all data recorded by the patient. Data from the patient assessments will be transcribed onto the appropriate Summary Data CRF page.
  • the patient assessment diary will be collected at the Final Visit.
  • the Study Nurse will review the patient assessment diary while the patient is still at the site. Data from the patient assessments will be transcribed onto the appropriate Summary Data CRF pages.
  • the patient assessment diary will be collected and reviewed and the patient will be queried about all adverse events experienced during the period between discharge from the unit and the Follow-up Visit. All adverse events will be recorded in the source documents and on the appropriate CRFs.
  • the patient will be queried about all medication taken during the period between discharge from the unit and the Follow-up Visit. Information about any concomitant medications will be transcribed onto the appropriate CRFs.
  • a completed patient is one who completes all of the 2-hour patient assessments. If for any reason a patient is withdrawn before completing the study or before Visit 2, the reason for withdrawal must be entered on the End of Study Form and all appropriate CRFs must be completed. All final assessments should be performed as described for Visit 2 (Follow-up Visit). Patients who terminate study participation before Visit 2 due to an adverse event will be reported as withdrawing due to an “adverse event.”
  • the Study Nurse will rate each patient for objective findings that confirm the diagnosis of tonsillo-pharyngitis at screening.
  • the seven variables below will be rated on semi-quantitative scales with values of 0, 1, 2, 3.
  • the values will be added together to make a Tonsillo-Pharyngitis Assessment (TPA) that can range from 0 to 21 points.
  • TPA Tonsillo-Pharyngitis Assessment
  • the patient must have a minimum of 5 points on the 21-point TPA of the physical examination to qualify for study inclusion:
  • the patient will be asked to evaluate his/her throat soreness using a 0-to-10 ordinal scale at Baseline as well as at 15, 30, 45, 60, 75, 90, 105 and 120 min and then hourly through 6 hours.
  • the patient will be requested to swallow and instructed:
  • the patient will be asked to evaluate his/her difficulty swallowing (dysphagia), how swollen the throat feels, and his/her difficulty speaking using separate 0-to-10 ordinal scales at Baseline and at 15, 30, 45, 60, 75, 90, 105, and 120 minutes and at 3, 4, 5, and 6 hours post dose.
  • the patient will be instructed to swallow and instructed:
  • the patient will be asked to evaluate 7 other sensory qualities of pain (hot, scratchy, raw, raspy, tight, dry, burning), 2 affective qualities of pain (irritating, annoying), and another evaluative quality of pain (it hurts) using separate 0-to-10 ordinal scales at Baseline and at 1 hour, 2 hours, and 6 hours post dose.
  • the patient will be instructed to swallow and instructed:
  • the patient will grade the improvement of his/her throat at 15, 30, 45, 60, 75, 90, 105, and 120 minutes, and at 3, 4, 5, and 6 hours post dose using a 5-category transitional scale.
  • the patient will be instructed:
  • the Study Nurse will separately show the patient his/her Baseline Difficulty Swallowing Scale, Swollen Throat Scale, Difficulty Talking Scale, and each of the 10 Quality-of-Pain Scales, with the same instructions for each scale.
  • An adverse event is any untoward medical occurrence in a clinical investigation patient administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. Examples of adverse events include but are not limited to:
  • a serious adverse event or serious adverse drug reaction is any untoward medical occurrence at any dose that:
  • a patient will be included in the Safety Population if the patient was randomized and swallowed the full dose of study medication.
  • the Safety Population will be used for the safety analysis. Patients in this population will be assigned to the treatment group corresponding to the treatment they received during the study.
  • Demographic and Baseline characteristics will be summarized using descriptive statistics, including the number of patients in each treatment group, mean, standard deviation, median and range for continuous variables; frequency and percent for categorical variables; etc.
  • sample size (9 patients per treatment group) is considered sufficient for proof-of-concept research. Statistical analyses will be performed when feasible, but it is not anticipated that there will be sizable treatment differences for statistical comparisons between treatment groups.
  • Patients who qualify will be assigned at the site in the order in which they are enrolled in the study. They will receive their allocated treatment according to a computer-generated randomization schedule prepared prior to the start of the study.
  • Efficacy data that can be analyzed will be analyzed using the Efficacy Population. All comparisons will be one-sided at an alpha level of 0.05 and all point estimates will be accompanied by 95% confidence intervals.
  • the primary endpoint variable is the Summed Difference in Throat Soreness at 6 hours, which is based on the Throat Soreness Scale.
  • the patient will be asked to evaluate his/her throat soreness, using a 0-to-10 ordinal scale at baseline and at 15, 30, 45, 60, 75, 90, 105 minutes and 2, 3, 4, 5, and 6 hours.
  • a difference is calculated between the throat soreness at that time and the patient's baseline throat soreness.
  • the time-weighted Summed Difference in Throat Soreness at each time point is calculated as the sum of the differences from baseline until that time point.
  • the Summed Difference in Throat Soreness at 6 hours will be displayed and analyzed by comparing treatment groups (e.g., ibuprofen 200 mg with hydroxyzine 50 mg to ibuprofen 200 mg) using a general linear model with treatment and baseline Throat Soreness as fixed effects.
  • treatment groups e.g., ibuprofen 200 mg with hydroxyzine 50 mg to ibuprofen 200 mg
  • the difference and 95% confidence interval for the difference of treatment effects will be calculated using least squares means. Alternate methods of display and analysis may be used when appropriate (including sub-analyses based on cogent clinical features such as relatively high baseline throat soreness, difficulty swallowing, swollen throat).
  • results for improvement and differences from baseline will be reported and displayed for individual patients and as medians, percentage differences, etc.
  • Alternate methods of display and analysis will be examined, including sub-analyses based on cogent clinical features (such as relatively high baseline difficulty swallowing, throat soreness, swollen throat) and based on the pharmacologic time-effect curves of the drugs being tested (i.e., onset time within the first 2 hours after drug administration).
  • results over the 6-hour observation period are presented separately for the standard measurement instrument, the Throat Soreness Scale, and for each new method.
  • TSS Throat Soreness Scale
  • the comparison of ibuprofen/loratadine to ibuprofen revealed an 11% difference in the median total reduction of TSS over 6 hours.
  • the comparison of ibuprofen/hydroxyzine to ibuprofen revealed a 22% difference in TSS reduction over 6 hours.
  • All active single- and combination-ingredient drugs also demonstrated greater analgesic efficacy compared with placebo in terms of throat soreness difference at individual time points, showing pharmacodynamic curves typical of analgesic drugs.
  • Acetaminophen separated from placebo from 15 minutes through 6 hours; ibuprofen separated from placebo from 30 minutes through 6 hours ( FIG. 3 ), as did naproxen and celecoxib. There were no apparent differences between any of the single-ingredient analgesics.
  • TSS scores showed differences from placebo for ibuprofen/loratadine beginning at 15 minutes; for ibuprofen/nizatidine and for celecoxib/ceterizine beginning at 30 minutes; and for ibuprofen/hydroxyzine beginning at 45 minutes.
  • Ceterizine showed some enhancement of the onset of analgesic action by celecoxib, suggesting that an adequately sized onset-of-action study might discern this contribution to pharmacodynamic activity. Overall, however, there was no evidence on the TSS of analgesic potentiation by ceterizine when combined with acetaminophen or celecoxib. And, while loratadine does augment ibuprofen's analgesia as measured on the TSS, at this stage in our research it appears that loratadine provides no detectable analgesic potentiation when combined with naproxen sodium (suggesting that the naproxen sodium salt, unlike ibuprofen, may interfere with loratadine activity).
  • IA Improvement Assessment
  • 9/9 patients who received acetaminophen or ibuprofen achieved at least some improvement within 1 hour, as did 7/9 patients who received celecoxib or naproxen, compared with 4/9 patients who received placebo.
  • 9/9 patients who received ibuprofen/nizatidine, 8/9 patients who received acetaminophen/ceterizine or ibuprofen/hydroxyzine 7/9 patients who received ibuprofen/loratadine
  • 6/9 patients who received naproxen/loratadine achieved at least some improvement within 1 hour.
  • 8/9 patients who received acetaminophen achieved at least some improvement within 30 minutes, as did 6/9 patients who received ibuprofen, 4/9 patients who received naproxen, and 3/9 patients who received celecoxib, compared with 1/9 of patients who received placebo.
  • All active single- and combination-ingredient drugs also demonstrated greater improvement than placebo at individual time points, showing pharmacodynamic curves typical of analgesic drugs.
  • the IA curves for acetaminophen and ibuprofen separated from placebo from 30 minutes through 6 hours; celecoxib and naproxen from 45 minutes through 6 hours. There were no apparent differences between any of the single-ingredient analgesics.
  • IA scores showed differences from placebo for acetaminophen/ceterizine and ibuprofen/nizatidine beginning at 30 minutes; for ibuprofen/loratadine, ibuprofen/hydroxyzine, and celecoxib/ceterizine beginning at 45 minutes; and for naproxen/loratadine beginning at 60 minutes.
  • DIL Definite Improvement Level
  • the Definite Improvement Level system was thus validated as a measurement instrument. Using the DIL measure, differences were clearly seen between antihistamine/analgesic combinations and placebo on different rating scales. However, the DIL did not differentiate antihistamine/analgesic combinations from single analgesics perhaps because, as a nominal scale (i.e., definite improvement, no definite improvement), the DIL identifies the presence (or absence) of drug activity, not differences between degrees of response.
  • D. Difficulty Swallowing Scale (DSS) D. Difficulty Swallowing Scale
  • Ibuprofen/loratadine, ibuprofen/hydroxyzine, ibuprofen/nizatidine, and celecoxib/ceterizine also differed from placebo on this measurement.
  • the comparison of ibuprofen/loratadine to ibuprofen revealed an 18% difference in the total reduction of DSS over 6 hours.
  • the comparison of ibuprofen/hydroxyzine to ibuprofen revealed a 55% difference in DSS reduction over 6 hours.
  • the comparison of ibuprofen/nizatidine to ibuprofen revealed a 78% difference in DSS reduction over 6 hours.
  • All single- and combination-ingredient drugs also demonstrated greater analgesic efficacy compared with placebo in terms of a difference in difficulty swallowing at individual time points, showing pharmacodynamic curves typical of analgesic drugs.
  • loratadine does augment ibuprofen's analgesia as measured on the DSS, it appears that loratadine provides no detectable analgesic potentiation when combined with naproxen sodium (perhaps because the naproxen sodium salt interferes with loratadine activity).
  • DTS Difficulty Talking Scale
  • the comparison of ibuprofen/loratadine to ibuprofen revealed 80% difference in the total reduction of DTS over 6 hours ( FIG. 7 ).
  • the comparison of ibuprofen/hydroxyzine to ibuprofen revealed 40% difference in DTS reduction over 6 hours.
  • the comparison of ibuprofen/nizatidine to ibuprofen revealed 120% difference in DTS reduction over 6 hours.
  • All single- and combination-ingredient drugs also demonstrated greater analgesic efficacy compared with placebo in terms of a difference in difficulty talking at individual time points, showing pharmacodynamic curves typical of analgesic drugs.
  • All single- and combination-ingredient drugs also demonstrated greater analgesic efficacy compared with placebo in terms of a difference in throat function at individual time points, showing pharmacodynamic curves typical of analgesic drugs.
  • the comparison of ibuprofen/loratadine to ibuprofen revealed 250% difference in the reduction of qualities of throat pain over 6 hours ( FIG. 10 ).
  • the comparison of ibuprofen/hydroxyzine to ibuprofen revealed 130% difference in the reduction of qualities of throat pain over 6 hours.
  • the new scales used herein also identified differences between antihistamine/analgesic combinations and the respective single analgesics Several new measurement instruments (e.g., Difficulty Swallowing Scale, Difficulty Talking Scale, Throat Function Index, Swollen Throat Scale, Qualities of Pain Index) described herein indicated that hydroxyzine, loratadine, and nizatidine enhance the analgesic properties of ibuprofen.
  • ibuprofen 200 mg/nizatadine 150 mg from ibuprofen 200 mg suggests, too, that this combination may confer the same or greater extent of analgesia as a 400-mg dose of ibuprofen (thus avoiding potential side effects associated with high dosages of NSAIDs), an example of “optimal analgesia” in the antihistamine/analgesic combination.

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170073313A1 (en) * 2014-05-06 2017-03-16 Purdue Pharma L.P. BENZOMORPHAN ANALOGS And Use Thereof
US11324727B2 (en) 2020-07-15 2022-05-10 Schabar Research Associates, Llc Unit oral dose compositions composed of naproxen sodium and famotidine for the treatment of acute pain and the reduction of the severity of heartburn and/or the risk of heartburn
US11331307B2 (en) 2020-07-15 2022-05-17 Schabar Research Associates, Llc Unit oral dose compositions composed of ibuprofen and famotidine for the treatment of acute pain and the reduction of the severity and/or risk of heartburn

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102247371A (zh) * 2011-08-19 2011-11-23 北京阜康仁生物制药科技有限公司 一种以布洛芬和拉呋替丁为活性成分的药物组合物
WO2015023675A2 (fr) 2013-08-12 2015-02-19 Pharmaceutical Manufacturing Research Services, Inc. Comprimé extrudé anti-abus à libération immédiate
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
WO2015095391A1 (fr) 2013-12-17 2015-06-25 Pharmaceutical Manufacturing Research Services, Inc. Comprimé extrudé anti-abus à libération prolongée
EP3169315B1 (fr) 2014-07-17 2020-06-24 Pharmaceutical Manufacturing Research Services, Inc. Forme posologique remplie de liquide anti-abus à libération immédiate
EP3209282A4 (fr) 2014-10-20 2018-05-23 Pharmaceutical Manufacturing Research Services, Inc. Forme galénique anti-abus de remplissage de liquide à libération prolongée
US10420756B2 (en) * 2015-03-26 2019-09-24 Sen-Jam Pharmaceutical Llc. Methods and compositions to inhibit symptoms associated with veisalgia
US10691774B2 (en) * 2015-03-30 2020-06-23 Cambia Health Solutions, Inc. Systems and methods for a comprehensive online health care platform
WO2019133760A1 (fr) * 2017-12-28 2019-07-04 NEUGATE PHARMA, LLC aka NEUGATE THERANOSTICS Compositions et formulations pour le traitement de tumeurs malignes
CN112259179A (zh) * 2020-10-09 2021-01-22 首都医科大学宣武医院 一种患者日志生成方法及装置
US11977085B1 (en) 2023-09-05 2024-05-07 Elan Ehrlich Date rape drug detection device and method of using same

Citations (93)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4230717A (en) 1978-12-29 1980-10-28 Lovelace Alan M Administrator Indomethacin-antihistamine combination for gastric ulceration control
US4279906A (en) 1977-11-10 1981-07-21 Nasa Indomethacin-antihistamine combination for gastric ulceration control
US4283408A (en) 1979-08-02 1981-08-11 Yamanouchi Pharmaceutical Co., Ltd. Guanidinothiazole compounds, process for preparation and gastric inhibiting compositions containing them
US4554276A (en) 1983-10-03 1985-11-19 Pfizer Inc. 2-Amino-5-hydroxy-4-methylpyrimidine derivatives
US4567183A (en) 1983-03-11 1986-01-28 Analgesic Associates Analgesic and anti-inflammatory compositions comprising xanthines and methods of using same
US4599359A (en) * 1982-12-09 1986-07-08 Stephen A. Cooper Hydroxyzine-containing analgesic combinations
US4683243A (en) 1984-02-08 1987-07-28 Richardson-Vicks, Inc. Analgesic and anti-inflammatory compositions comprising diphenhydramine and methods of using same
US4755532A (en) 1984-02-08 1988-07-05 Richardson-Vicks, Inc. Analgesic and anti-inflammatory compositions comprising diphenhydramine and methods of using same
US4757060A (en) 1986-03-04 1988-07-12 Bristol-Myers Company Non-steroidal anti-inflammatory compositions protected against gastrointestinal injury with a combination of certain H1 and H2, receptor blockers
US4783465A (en) 1984-04-09 1988-11-08 Analgesic Associates Cough/cold mixtures comprising non-sedating antihistamine drugs
US4794112A (en) 1982-12-09 1988-12-27 Cooper Stephen A Acetaminophen/hydroxyzine analgesic combinations
US4829064A (en) 1987-06-08 1989-05-09 Analgesic Associates Cough/cold mixtures comprising non-sedating antihistamine drugs
US4871733A (en) 1984-04-09 1989-10-03 Analgesic Associates Cough/cold mixtures comprising non-sedating antihistamine drugs
US4975426A (en) 1987-06-08 1990-12-04 Analgesic Associates Cough/cold mixtures comprising non-sedating antihistamine drugs
US4990535A (en) 1989-05-03 1991-02-05 Schering Corporation Pharmaceutical composition comprising loratadine, ibuprofen and pseudoephedrine
US4994327A (en) 1981-06-19 1991-02-19 Kanegafuchi Kogaku Kogyo Kabushiki Kaisha Coated article with metallic finish
US5009875A (en) 1988-08-03 1991-04-23 International Dioxcide, Inc. Process of preparing clorine dioxide and apparatus therefor
EP0426479A1 (fr) 1989-11-02 1991-05-08 McNEIL-PPC, INC. Utilisation d'une compostition pour la fabrication d'un médicament destiné à traiter les symptômes de l'intempérance
US5037815A (en) 1986-03-04 1991-08-06 Bristol-Myers Squibb Co. Non-steroidal anti-inflammatory compositions protected against gastrointestinal injury with a combination of certain H1 - and H2 -receptor blockers
US5102902A (en) 1973-06-18 1992-04-07 Mercer James B Reagents and method for therapeutic treatment of multiple sclerosis
WO1992005783A1 (fr) 1990-09-28 1992-04-16 Merck & Co., Inc. Combinaisons d'ibuprofene-antihistamine
US5204118A (en) 1989-11-02 1993-04-20 Mcneil-Ppc, Inc. Pharmaceutical compositions and methods for treating the symptoms of overindulgence
US5229137A (en) 1992-05-06 1993-07-20 Brigham And Women's Hospital, Inc. Methods and pharmaceutical compositions for treating episodic heartburn
WO1994007541A1 (fr) 1992-09-29 1994-04-14 Merck & Co., Inc. Combinaisons d'ibuprofene-antihistaminique anti-h¿2?
US5362737A (en) 1991-04-09 1994-11-08 Chemex Pharmaceuticals, Inc. Methods of treating aphthous ulcers and other mucocutaneous disorders with amlexanox
US5541212A (en) 1994-01-10 1996-07-30 Metatron, Inc. Use of cimetidine for the control of retrovirus infections
US5578597A (en) 1993-10-13 1996-11-26 Merck & Co., Inc. Combination therapy for HIV infection
US5594276A (en) 1992-03-03 1997-01-14 Sgs-Thomson Microelectronics, S.A. Semiconductor device package with shaped parts for direct coupling to standard connectors
US5718919A (en) * 1995-02-24 1998-02-17 Nanosystems L.L.C. Nanoparticles containing the R(-)enantiomer of ibuprofen
US5763422A (en) 1995-01-27 1998-06-09 Board Of Regents, The University Of Texas System Methods of enhancing the therapeutic activity of NSAIDS and compositions of zwitterionic phospholipids useful therein
US5805580A (en) 1995-02-06 1998-09-08 Alcatel N.V. Cell Switching Network
US5955451A (en) 1995-05-12 1999-09-21 The University Of Texas System Board Of Regents Methods of enhancing the therapeutic activity of NSAIDS and compositions of zwitterionic phospholipids useful therein
US5993327A (en) 1998-05-19 1999-11-30 Terry Terril Golf putting device and method of using the same to putt a golf ball
US6004582A (en) 1997-05-30 1999-12-21 Laboratorios Phoenix U.S.A, Inc. Multi-layered osmotic device
US6027746A (en) 1997-04-23 2000-02-22 Warner-Lambert Company Chewable soft gelatin-encapsulated pharmaceutical adsorbates
WO2000035298A1 (fr) 1996-11-27 2000-06-22 Wm. Wrigley Jr. Company Chewing-gum contenant des agents medicamenteux actifs
US6130233A (en) 1992-09-03 2000-10-10 Sepracor Inc. Methods and compositions for treating allergic disorders and other disorders using metabolic derivatives of astemizole
US6146661A (en) 1995-10-03 2000-11-14 Chugai Seiyaku Kabushiki Kaisha Chewable tablet
US6160020A (en) 1996-12-20 2000-12-12 Mcneill-Ppc, Inc. Alkali metal and alkaline-earth metal salts of acetaminophen
US6248363B1 (en) 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
WO2001043722A2 (fr) 1999-12-17 2001-06-21 Atrix Laboratories, Inc. Formulations de gels et d'aerosols pharmaceutiques et methodes pour les appliquer sur la peau et les muqueuses
US6261602B1 (en) 1996-10-23 2001-07-17 Eurand International S.P.A. Pharmaceutical composition for rapid suspension in aqueous media
US6270807B1 (en) 1999-03-02 2001-08-07 L. Perrigo Company Taste-masked pharmaceutical composition
US6294192B1 (en) 1999-02-26 2001-09-25 Lipocine, Inc. Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents
US6303632B1 (en) 1992-09-03 2001-10-16 Sepracor Inc. Compositions for treating allergic and other disorders using norastemizole in combination with other active ingredients
US6384038B1 (en) 1998-04-14 2002-05-07 Sepracor Inc. Methods and compositions using cetirizine in combination with leukotriene inhibitors or decongestants
US6395300B1 (en) 1999-05-27 2002-05-28 Acusphere, Inc. Porous drug matrices and methods of manufacture thereof
US6417184B1 (en) 2000-09-19 2002-07-09 David M. Ockert Triple drug therapy for the treatment and prevention of acute or chronic pain
US6471991B2 (en) 1998-08-18 2002-10-29 Mcneil-Ppc, Inc. Soft chewable tablets having convexed shaped face surfaces
WO2003026627A1 (fr) 2001-09-28 2003-04-03 Mcneil-Ppc, Inc. Formes pharmaceutiques composites
US6552047B2 (en) 1998-11-17 2003-04-22 Nitromed, Inc. H2 receptor antagonist compounds in combination with nitric oxide donors, compositions and methods of use
US6589551B1 (en) 1998-07-02 2003-07-08 Reckitt Benckiser Healthcare (Uk) Limited Chewable oral unit dosage
US6589556B2 (en) 2000-07-05 2003-07-08 Capricorn Pharma, Inc. Rapid-melt semi-solid compositions, methods of making same and methods of using same
US20030130263A1 (en) 2001-12-05 2003-07-10 Peirce Management,Llc Compositions containing both sedative and non-sedative antihistamines
US6596298B2 (en) 1998-09-25 2003-07-22 Warner-Lambert Company Fast dissolving orally comsumable films
US6610667B1 (en) 1999-05-05 2003-08-26 Reckitt Benckiser Healthcare (Uk) Limited Compositions for treatment of disorders of the oesophagus
US6627235B2 (en) 1996-02-15 2003-09-30 Puratos N.V. Process for obtaining improved structure build-up of baked products
US6656482B2 (en) 1998-06-03 2003-12-02 Taro Pharmaceutical Industries Ltd. Spill resistant pharmaceutical system
US6663893B2 (en) 2000-04-20 2003-12-16 Bristol-Myers Squibb Co. Taste masking coating composition
US20040029864A1 (en) 2002-02-04 2004-02-12 Pharmacia Corporation Treatment of colds and cough with a combination of a cyclooxygenase-2 selective inhibitor and a colds and cough active ingredient and compositions thereof
US6713089B1 (en) 1998-09-10 2004-03-30 Nycomed Danmark A/S Quick release pharmaceutical compositions of drug substances
US6773721B1 (en) 1992-11-02 2004-08-10 Alza Corporation Osmotic caplet
US20050008690A1 (en) 2002-04-10 2005-01-13 Miller Fred H. Multi-phase, multi-compartment capsular delivery apparatus and methods for using same
US20050095197A1 (en) 2003-10-31 2005-05-05 Tuszynski Jack A. Anti-mitotic compound
WO2005063219A2 (fr) 2003-12-23 2005-07-14 Ranbaxy Laboratories Limited Capsules en gelatine molle contenant de l'ibuprofene
US20050163847A1 (en) 2004-01-21 2005-07-28 Andrx Pharmaceuticals, Llc Pharmaceutical formulations containing a non-steroidal antiinflammatory drug and an antiulcerative drug
US6926907B2 (en) 2001-06-01 2005-08-09 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US6951871B2 (en) 2002-06-24 2005-10-04 Schering Corporation Indole derivatives useful as histamine H3 antagonists
US20060034943A1 (en) 2003-10-31 2006-02-16 Technology Innovations Llc Process for treating a biological organism
WO2006052856A1 (fr) 2004-11-04 2006-05-18 Reliant Pharmaceuticals, Inc. Traitement a la nizatidine et systeme correspondant
US7105505B2 (en) 2002-04-18 2006-09-12 Schering Corporation Benzimidazole derivatives useful as histamine H3 antagonists
US20070043097A1 (en) 2005-07-18 2007-02-22 Horizon Therapeutics, Inc. Medicaments containing famotidine and ibuprofen and administration of same
US7186753B1 (en) 1999-08-12 2007-03-06 Nicox S.A. Pharmaceutical compounds
US7220735B2 (en) 2002-04-18 2007-05-22 Schering Corporation Benzimidazolone histamine H3 antagonists
US20070154542A1 (en) * 2005-12-30 2007-07-05 Cogentus Pharmaceuticals, Inc. Oral pharmaceutical formulations containing non-steroidal anti-inflammatory drugs and acid inhibitors
US7271266B2 (en) 2002-03-28 2007-09-18 Merck & Co., Inc. Substituted 2,3-diphenyl pyridines
WO2007072503A3 (fr) 2005-12-21 2007-11-01 Panacea Biotec Ltd Compositions pour traiter des inflammations et desordres similaires
US7300941B2 (en) 2000-10-17 2007-11-27 Schering Corporation Non-imidazole compounds
US20080020040A1 (en) 2006-07-18 2008-01-24 Horizon Therapeutics, Inc. Unit dose form for administration of ibuprofen
US20080021078A1 (en) 2006-07-18 2008-01-24 Horizon Therapeutics, Inc. Methods and medicaments for administration of ibuprofen
US7323129B2 (en) 2001-09-28 2008-01-29 Omj Ireland Limited Systems, methods and apparatuses for manufacturing dosage forms
US20080050427A1 (en) 1997-09-17 2008-02-28 Purdue Pharma L.P. Analgesic combination of tramadol and meloxicam
US20080063706A1 (en) 2006-07-18 2008-03-13 Horizon Therapeutics, Inc. Methods and Medicaments for Administration of Ibuprofen
US7429575B2 (en) 2006-01-10 2008-09-30 Yu Ruey J N-(phosphonoalkyl)-amino acids, derivatives thereof and compositions and methods of use
US7482469B2 (en) 2005-11-08 2009-01-27 N.V. Organon 2-(benzimidazol-1-yl)-acetamide bisaryl derivatives
US20090142393A1 (en) 2007-11-30 2009-06-04 Horizon Therapeutics, Inc. Stable Compositions of Famotidine and Ibuprofen
US20090275622A1 (en) 2008-04-30 2009-11-05 Prasoona Linga Nizatidine formulations
US7678786B2 (en) 2006-04-18 2010-03-16 Janssen Pharmaceutica Nv Benzoazepin-oxy-acetic acid derivatives as PPAR-delta agonists used for the increase of HDL-C, lower LDL-C and lower cholesterol
US7678387B2 (en) 2000-06-06 2010-03-16 Capricorn Pharma, Inc. Drug delivery systems
US7744908B2 (en) 2003-10-28 2010-06-29 Taro Pharmaceuticals U.S.A., Inc. Spill resistant formulations containing clays
US7749533B2 (en) 2003-05-07 2010-07-06 Akina, Inc. Highly plastic granules for making fast melting tablets
US7772232B2 (en) 2004-04-15 2010-08-10 Bristol-Myers Squibb Company Quinazolinyl compounds as inhibitors of potassium channel function
US20100297224A1 (en) 2006-08-31 2010-11-25 Horizon Therapeutics, Inc. NSAID Dose Unit Formulations with H2-Receptor Antagonists and Methods of Use

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090233970A1 (en) * 2008-03-11 2009-09-17 Nickell Robert P Combined nsaid and acid blocker formulation and method

Patent Citations (103)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5102902A (en) 1973-06-18 1992-04-07 Mercer James B Reagents and method for therapeutic treatment of multiple sclerosis
US4279906A (en) 1977-11-10 1981-07-21 Nasa Indomethacin-antihistamine combination for gastric ulceration control
US4230717A (en) 1978-12-29 1980-10-28 Lovelace Alan M Administrator Indomethacin-antihistamine combination for gastric ulceration control
US4283408A (en) 1979-08-02 1981-08-11 Yamanouchi Pharmaceutical Co., Ltd. Guanidinothiazole compounds, process for preparation and gastric inhibiting compositions containing them
US4994327A (en) 1981-06-19 1991-02-19 Kanegafuchi Kogaku Kogyo Kabushiki Kaisha Coated article with metallic finish
US4599359A (en) * 1982-12-09 1986-07-08 Stephen A. Cooper Hydroxyzine-containing analgesic combinations
US4794112A (en) 1982-12-09 1988-12-27 Cooper Stephen A Acetaminophen/hydroxyzine analgesic combinations
US4567183A (en) 1983-03-11 1986-01-28 Analgesic Associates Analgesic and anti-inflammatory compositions comprising xanthines and methods of using same
US4554276A (en) 1983-10-03 1985-11-19 Pfizer Inc. 2-Amino-5-hydroxy-4-methylpyrimidine derivatives
US4683243A (en) 1984-02-08 1987-07-28 Richardson-Vicks, Inc. Analgesic and anti-inflammatory compositions comprising diphenhydramine and methods of using same
US4755532A (en) 1984-02-08 1988-07-05 Richardson-Vicks, Inc. Analgesic and anti-inflammatory compositions comprising diphenhydramine and methods of using same
US4871733A (en) 1984-04-09 1989-10-03 Analgesic Associates Cough/cold mixtures comprising non-sedating antihistamine drugs
US4783465A (en) 1984-04-09 1988-11-08 Analgesic Associates Cough/cold mixtures comprising non-sedating antihistamine drugs
US5037815A (en) 1986-03-04 1991-08-06 Bristol-Myers Squibb Co. Non-steroidal anti-inflammatory compositions protected against gastrointestinal injury with a combination of certain H1 - and H2 -receptor blockers
US4757060A (en) 1986-03-04 1988-07-12 Bristol-Myers Company Non-steroidal anti-inflammatory compositions protected against gastrointestinal injury with a combination of certain H1 and H2, receptor blockers
US4975426A (en) 1987-06-08 1990-12-04 Analgesic Associates Cough/cold mixtures comprising non-sedating antihistamine drugs
US4829064A (en) 1987-06-08 1989-05-09 Analgesic Associates Cough/cold mixtures comprising non-sedating antihistamine drugs
US5009875A (en) 1988-08-03 1991-04-23 International Dioxcide, Inc. Process of preparing clorine dioxide and apparatus therefor
US5100675A (en) 1989-05-03 1992-03-31 Schering Corporation Sustained release tablet comprising loratadine, ibuprofen and pseudoephedrine
US4990535A (en) 1989-05-03 1991-02-05 Schering Corporation Pharmaceutical composition comprising loratadine, ibuprofen and pseudoephedrine
EP0426479A1 (fr) 1989-11-02 1991-05-08 McNEIL-PPC, INC. Utilisation d'une compostition pour la fabrication d'un médicament destiné à traiter les symptômes de l'intempérance
US5417980A (en) 1989-11-02 1995-05-23 Mcneil-Ppc, Inc. Pharmaceutical compositions and methods for treating the symptoms of overindulgence
US5204118A (en) 1989-11-02 1993-04-20 Mcneil-Ppc, Inc. Pharmaceutical compositions and methods for treating the symptoms of overindulgence
WO1992005783A1 (fr) 1990-09-28 1992-04-16 Merck & Co., Inc. Combinaisons d'ibuprofene-antihistamine
US5362737A (en) 1991-04-09 1994-11-08 Chemex Pharmaceuticals, Inc. Methods of treating aphthous ulcers and other mucocutaneous disorders with amlexanox
US5594276A (en) 1992-03-03 1997-01-14 Sgs-Thomson Microelectronics, S.A. Semiconductor device package with shaped parts for direct coupling to standard connectors
US5229137A (en) 1992-05-06 1993-07-20 Brigham And Women's Hospital, Inc. Methods and pharmaceutical compositions for treating episodic heartburn
US6303632B1 (en) 1992-09-03 2001-10-16 Sepracor Inc. Compositions for treating allergic and other disorders using norastemizole in combination with other active ingredients
US6187795B1 (en) 1992-09-03 2001-02-13 Sepracor Inc. Methods and compositions for treating allergic disorders and other disorders using norastemizole in combination with other active ingredients
US6130233A (en) 1992-09-03 2000-10-10 Sepracor Inc. Methods and compositions for treating allergic disorders and other disorders using metabolic derivatives of astemizole
US6384054B1 (en) 1992-09-03 2002-05-07 Sepracor Inc. Compositions for treating allergic and other disorders using norastemizole in combination with other active ingredients
WO1994007541A1 (fr) 1992-09-29 1994-04-14 Merck & Co., Inc. Combinaisons d'ibuprofene-antihistaminique anti-h¿2?
US6773721B1 (en) 1992-11-02 2004-08-10 Alza Corporation Osmotic caplet
US5578597A (en) 1993-10-13 1996-11-26 Merck & Co., Inc. Combination therapy for HIV infection
US5541212A (en) 1994-01-10 1996-07-30 Metatron, Inc. Use of cimetidine for the control of retrovirus infections
US5763422A (en) 1995-01-27 1998-06-09 Board Of Regents, The University Of Texas System Methods of enhancing the therapeutic activity of NSAIDS and compositions of zwitterionic phospholipids useful therein
US5805580A (en) 1995-02-06 1998-09-08 Alcatel N.V. Cell Switching Network
US5718919A (en) * 1995-02-24 1998-02-17 Nanosystems L.L.C. Nanoparticles containing the R(-)enantiomer of ibuprofen
US5955451A (en) 1995-05-12 1999-09-21 The University Of Texas System Board Of Regents Methods of enhancing the therapeutic activity of NSAIDS and compositions of zwitterionic phospholipids useful therein
US6146661A (en) 1995-10-03 2000-11-14 Chugai Seiyaku Kabushiki Kaisha Chewable tablet
US6627235B2 (en) 1996-02-15 2003-09-30 Puratos N.V. Process for obtaining improved structure build-up of baked products
US6261602B1 (en) 1996-10-23 2001-07-17 Eurand International S.P.A. Pharmaceutical composition for rapid suspension in aqueous media
WO2000035298A1 (fr) 1996-11-27 2000-06-22 Wm. Wrigley Jr. Company Chewing-gum contenant des agents medicamenteux actifs
US6160020A (en) 1996-12-20 2000-12-12 Mcneill-Ppc, Inc. Alkali metal and alkaline-earth metal salts of acetaminophen
US6027746A (en) 1997-04-23 2000-02-22 Warner-Lambert Company Chewable soft gelatin-encapsulated pharmaceutical adsorbates
US6004582A (en) 1997-05-30 1999-12-21 Laboratorios Phoenix U.S.A, Inc. Multi-layered osmotic device
US20080050427A1 (en) 1997-09-17 2008-02-28 Purdue Pharma L.P. Analgesic combination of tramadol and meloxicam
US6384038B1 (en) 1998-04-14 2002-05-07 Sepracor Inc. Methods and compositions using cetirizine in combination with leukotriene inhibitors or decongestants
US5993327A (en) 1998-05-19 1999-11-30 Terry Terril Golf putting device and method of using the same to putt a golf ball
US6656482B2 (en) 1998-06-03 2003-12-02 Taro Pharmaceutical Industries Ltd. Spill resistant pharmaceutical system
US6589551B1 (en) 1998-07-02 2003-07-08 Reckitt Benckiser Healthcare (Uk) Limited Chewable oral unit dosage
US6471991B2 (en) 1998-08-18 2002-10-29 Mcneil-Ppc, Inc. Soft chewable tablets having convexed shaped face surfaces
US6713089B1 (en) 1998-09-10 2004-03-30 Nycomed Danmark A/S Quick release pharmaceutical compositions of drug substances
US7407669B2 (en) 1998-09-25 2008-08-05 Mcneil-Ppc, Inc. Fast dissolving orally consumable films
US6596298B2 (en) 1998-09-25 2003-07-22 Warner-Lambert Company Fast dissolving orally comsumable films
US6552047B2 (en) 1998-11-17 2003-04-22 Nitromed, Inc. H2 receptor antagonist compounds in combination with nitric oxide donors, compositions and methods of use
US6294192B1 (en) 1999-02-26 2001-09-25 Lipocine, Inc. Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents
US6270807B1 (en) 1999-03-02 2001-08-07 L. Perrigo Company Taste-masked pharmaceutical composition
US6610667B1 (en) 1999-05-05 2003-08-26 Reckitt Benckiser Healthcare (Uk) Limited Compositions for treatment of disorders of the oesophagus
US6395300B1 (en) 1999-05-27 2002-05-28 Acusphere, Inc. Porous drug matrices and methods of manufacture thereof
US7186753B1 (en) 1999-08-12 2007-03-06 Nicox S.A. Pharmaceutical compounds
US6248363B1 (en) 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
WO2001043722A2 (fr) 1999-12-17 2001-06-21 Atrix Laboratories, Inc. Formulations de gels et d'aerosols pharmaceutiques et methodes pour les appliquer sur la peau et les muqueuses
US6663893B2 (en) 2000-04-20 2003-12-16 Bristol-Myers Squibb Co. Taste masking coating composition
US7678387B2 (en) 2000-06-06 2010-03-16 Capricorn Pharma, Inc. Drug delivery systems
US6589556B2 (en) 2000-07-05 2003-07-08 Capricorn Pharma, Inc. Rapid-melt semi-solid compositions, methods of making same and methods of using same
US6417184B1 (en) 2000-09-19 2002-07-09 David M. Ockert Triple drug therapy for the treatment and prevention of acute or chronic pain
US7300941B2 (en) 2000-10-17 2007-11-27 Schering Corporation Non-imidazole compounds
US6926907B2 (en) 2001-06-01 2005-08-09 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
WO2003026627A1 (fr) 2001-09-28 2003-04-03 Mcneil-Ppc, Inc. Formes pharmaceutiques composites
US7361006B2 (en) 2001-09-28 2008-04-22 Mcneil-Ppc, Inc. Systems, methods and apparatuses for manufacturing dosage forms
US7323129B2 (en) 2001-09-28 2008-01-29 Omj Ireland Limited Systems, methods and apparatuses for manufacturing dosage forms
US20030130263A1 (en) 2001-12-05 2003-07-10 Peirce Management,Llc Compositions containing both sedative and non-sedative antihistamines
US20040029864A1 (en) 2002-02-04 2004-02-12 Pharmacia Corporation Treatment of colds and cough with a combination of a cyclooxygenase-2 selective inhibitor and a colds and cough active ingredient and compositions thereof
US7271266B2 (en) 2002-03-28 2007-09-18 Merck & Co., Inc. Substituted 2,3-diphenyl pyridines
US20050008690A1 (en) 2002-04-10 2005-01-13 Miller Fred H. Multi-phase, multi-compartment capsular delivery apparatus and methods for using same
US7670612B2 (en) 2002-04-10 2010-03-02 Innercap Technologies, Inc. Multi-phase, multi-compartment capsular delivery apparatus and methods for using same
US7105505B2 (en) 2002-04-18 2006-09-12 Schering Corporation Benzimidazole derivatives useful as histamine H3 antagonists
US7220735B2 (en) 2002-04-18 2007-05-22 Schering Corporation Benzimidazolone histamine H3 antagonists
US6951871B2 (en) 2002-06-24 2005-10-04 Schering Corporation Indole derivatives useful as histamine H3 antagonists
US7749533B2 (en) 2003-05-07 2010-07-06 Akina, Inc. Highly plastic granules for making fast melting tablets
US7744908B2 (en) 2003-10-28 2010-06-29 Taro Pharmaceuticals U.S.A., Inc. Spill resistant formulations containing clays
US20050095197A1 (en) 2003-10-31 2005-05-05 Tuszynski Jack A. Anti-mitotic compound
US20060034943A1 (en) 2003-10-31 2006-02-16 Technology Innovations Llc Process for treating a biological organism
WO2005063219A2 (fr) 2003-12-23 2005-07-14 Ranbaxy Laboratories Limited Capsules en gelatine molle contenant de l'ibuprofene
US20050163847A1 (en) 2004-01-21 2005-07-28 Andrx Pharmaceuticals, Llc Pharmaceutical formulations containing a non-steroidal antiinflammatory drug and an antiulcerative drug
US7772232B2 (en) 2004-04-15 2010-08-10 Bristol-Myers Squibb Company Quinazolinyl compounds as inhibitors of potassium channel function
WO2006052856A1 (fr) 2004-11-04 2006-05-18 Reliant Pharmaceuticals, Inc. Traitement a la nizatidine et systeme correspondant
US20070043096A1 (en) 2005-07-18 2007-02-22 Horizon Therapeutics, Inc. Unit dose form with ibuprofen-famotidine admixture
US20070043097A1 (en) 2005-07-18 2007-02-22 Horizon Therapeutics, Inc. Medicaments containing famotidine and ibuprofen and administration of same
US7482469B2 (en) 2005-11-08 2009-01-27 N.V. Organon 2-(benzimidazol-1-yl)-acetamide bisaryl derivatives
WO2007072503A3 (fr) 2005-12-21 2007-11-01 Panacea Biotec Ltd Compositions pour traiter des inflammations et desordres similaires
US20070154542A1 (en) * 2005-12-30 2007-07-05 Cogentus Pharmaceuticals, Inc. Oral pharmaceutical formulations containing non-steroidal anti-inflammatory drugs and acid inhibitors
US20100227854A1 (en) 2005-12-30 2010-09-09 Horizon Therapeutics, Inc. Oral Pharmaceutical Formulations Containing Non-Steroidal Anti-Inflammatory Drugs and Acid Inhibitors
US7429575B2 (en) 2006-01-10 2008-09-30 Yu Ruey J N-(phosphonoalkyl)-amino acids, derivatives thereof and compositions and methods of use
US7678786B2 (en) 2006-04-18 2010-03-16 Janssen Pharmaceutica Nv Benzoazepin-oxy-acetic acid derivatives as PPAR-delta agonists used for the increase of HDL-C, lower LDL-C and lower cholesterol
US20090264484A1 (en) 2006-07-18 2009-10-22 Horizon Therapeutics, Inc. Methods and Medicaments for Administration of Ibuprofen
US20080020040A1 (en) 2006-07-18 2008-01-24 Horizon Therapeutics, Inc. Unit dose form for administration of ibuprofen
US20080063706A1 (en) 2006-07-18 2008-03-13 Horizon Therapeutics, Inc. Methods and Medicaments for Administration of Ibuprofen
US20080021078A1 (en) 2006-07-18 2008-01-24 Horizon Therapeutics, Inc. Methods and medicaments for administration of ibuprofen
US20100297224A1 (en) 2006-08-31 2010-11-25 Horizon Therapeutics, Inc. NSAID Dose Unit Formulations with H2-Receptor Antagonists and Methods of Use
US20090142393A1 (en) 2007-11-30 2009-06-04 Horizon Therapeutics, Inc. Stable Compositions of Famotidine and Ibuprofen
US20090275622A1 (en) 2008-04-30 2009-11-05 Prasoona Linga Nizatidine formulations

Non-Patent Citations (46)

* Cited by examiner, † Cited by third party
Title
A Bartlett et al. The effect of antacid and ranitidine on droxicam pharmacokinetics. J. Clin. Pharmacol. 1992; 32 (12): 1115-1119.
A Leucuta et al. No effect of short term ranitidine on diclofenac pharmacokinetics. Rom. J. Gastroenterol. 2004; 13 (4): 306-308.
Andersson et al., "Lack of drug-drug interaction between three different non-steroidal anti-inflammatory drugs and omeprazole" Eur. J. Clin. Pharmacol., 1998; 54: 399-404.
Australian Examination Report for application No. 2009204360 dated Apr. 26, 2013.
B Delhotal-Landes et al. Pharmacokinetic interations between NSAIDs (indomethacin or sulindac) and H2-receptor antagonists (cimetidine or ranitidine) in human volunteers. Clin. Pharmacol. Ther. 1988; 44 (4): 442-452.
Birk et al. "A fixed dose combination of ibuprofen and famotidine,", 2009 Expert Opin. Investig. Drugs 18: 1385-1391.
Bluhm et al., Potentiation of Opoid Anagesia by H1 and H2 Antagonists, Life Sciences, vol. 31, Issues 12-13, Sep. 1982, pp. 1229-1232.
European Search Report dated Dec. 8, 2011 for EP application No. 09700489.9.
Evans et al., "Lack of effect of cimetidine on the pharmacokinetics of R-(-) and S-(+) ibuprofen" Br. J. Clin. Pharmacol., 1989; 28: 143-149.
Evans et al., "Lack of effect of cimetidine on the pharmacokinetics of R-(−) and S-(+) ibuprofen" Br. J. Clin. Pharmacol., 1989; 28: 143-149.
First Examination Report dated Feb. 22, 2011 for New Zealand application No. 587202.
Forsyth et al. "Do Nizatidine and Cimetidine Interact with Ibuprofen?" European Journal of Clinical Pharmacology, 1988, 85-8. Springer-Verlag, vol. 35.
HG Dammann et al. Differential effects of misoprostil and ranitidine on the pharmacokinetics of diclofenac and gastrointestinal symptoms. Br. J. Clin. Pharmacol. 1993; 36(4): 345-349.
Hough et al. "Novel Qualitative Structure-Activity Relationships for the Antinociceptive Actions of H2 Antagonists, H3 Antagonists and Derivatives," The Journal of Pharmacology and Experimental Therapeutics, 1997, 1534-43. The American Society for Pharmacology and Experimental Therapeutics, vol. 283.
International Search Report and Combination Written Opinion in re PCT/US2009/30079, mailed Feb. 26, 2009.
JS Dixon et al. A lack of pharmacokinetic interaction between ranitidine and piroxicam. Eur. J. Clin. Pharmacol. 1990; 39(6): 583-586.
Kendall et al., "Coadministration of misoprostol or ranitidine with indomethacin: effects on pharmacokinetics, abdominal symptoms and bowel habit" Aliment Pharmacol. Ther. 1992; 6;437-446.
Laska et al. "The correlation between blood levels of ibuprofen and clinical analgesic response," Clinical Pharmacology and Therapeutics, 1986, vol. 40, Abstract only.
M Ravic et al. A pharmacokinetic interaction between cimetidine or ranitidine and lornoxicam. Postgrad. Med. J. 1993; 69: 865-866.
N Bacracheva et al. Effect of cimetidine on the pharmacokinetics of the metabolites of metamizol. Int. J. Clin. Pharmacol. Ther. 1997; 35(7): 275-281. (abstract only).
Naproxen Report, 1983.
Ochs et al . "Interaction of ibuprofen with the H-2 receptor antagonists ranitidine and cimetidine," Clinical Pharmacology and Therapeutics, 1985, 648-51, vol. 38.
PA Milligan et al. The consequences of H2 receptor antagonist-piroxicam coadministration in patients with joint disorders. Eur. J. Clin. Pharmacol. 1993: 45(6): 507-512.
Parrott et al. "Influence of cimetidine on the disposition of ibuprofen in the rat," Research Communications in Chemical Pathology and Pharmacology, 1984, vol. 43, Abstract only.
Raffa R.B. "Antihistamines as analgesics," Journal of Clinical Pharmacology and Therapeutics, 2001, 81-5, vol. 26.
Response to First Examination Report dated May 22, 2012 for New Zealand application No. 587202.
Response to Office Action dated Jul. 6, 2012 for European Application No. 09700489.9.
Rumore and Schlichting, "Clinical Efficacy of Antihistaminics as Analgesics," Pain, 25, 1986, pp. 7-22.
SA Said et al. Influence of cimetidine on the pharmacokinetics of piroxicam in rat and man. Arzneimittelforschung 1989; 39(7): 790-792. (abstract only).
Santiago-Palmaet al. "Diphenhyramine as an Analgesic Adjuvant in Refractory Cancer Pain", Journal of Pain and Symptom Management, 2001, vol. 22., No. 2, pp. 699-703, Elsevier, New York.
Schachtel (1991) "Sore Throat Pain," Advances in Pain Research and Therapy, vol. 18, edited by M. Max, R. Portenoy, and E. Laska, Raven Press, Ltd., New York, pp. 393-407.
Schachtel and Thoden, (1993) "A placebo-controlled model for assaying systemic analgesics in children," Clin. Pharmacol. Ther. 53: 593-601.
Schachtel et al. (1984) "Rating Scales for Analgesics in Sore Throat," Clinical Pharmacology and Therapeutics, vol. 36, No. 2, pp. 151-156.
Schachtel et al. (1988) "Sore throat pain in the evaluation of mild anagesics," Clin. Pharmacol. and Therapeutics, vol. 44, No. 6, pp. 704-711.
Schachtel et al. (2007) "Utility and Sensitivity of the Sore Throat Pain Model: Results of a Randomized Controlled Trial on the COX-2 Selective Inhibitor Valdecoxib," J. Clin. Pharmacol. 47: 860, pp. 860-870. (Originally published online May 24, 2007).
Schachtel et al., (2002) "Demonstration of dose response of flurbiprofen lozenges with the sore throat pain model," Clin. Pharmacol. Ther. 71: 375-380.
Second Examination Report dated Jun. 13, 2012 for New Zealand application No. 587202.
Shamburek et al, "Control of gastric acid secretion. Histamine H2-receptor antagonists and H+K(+)-ATPase inhibitors." Medical College of Virginia, Richmond, Gastroenterol Clinic North America, Sep. 1992, 21(3):527-50, Abstract only provided.
Singh et al., "Gastrointestinal Tract Complications of Nonsteroidal Anti-inflammatory Drug Treatment in Rheumatoid Arthritis" Arch. Intern. Med., 1996; 156: 1530-1536.
Small et al., "Influence of H2-receptor antagonists on the disposition of flurbiprofen enantiomers" J. Clin. Pharmacol. 1990; 30: 660-664.
TB Vree et al. The effects of cimetidine, ranitidine, and famotidine on the single-dose pharmacokinetics of naproxen and its metabolites in humans. Int. J. Clin. Pharmacol. Ther. Toxicol. 1993; 31(12): 597-601. (abstract only).
TB Vree et al. The pharmacokinetics of naproxen, its metabolite O-desmethylnaproxen, and their acyl glucuronides in humans. Effect of cimetidine. Br. J. Clin. Pharmacol. 1993; 35(5): 467-472.
U Busch et al. Interaction of meloxicam with cimetidine, Maalox, or aspirin. J. Clin. Pharmacol. 1996; 36(1): 79-84.
Verbeeck et al. "Single and multiple dose pharmacokinetics of enteric coated ketoprofen: effect of cimetidine" Eur. J. Clin. Pharmacol. 1988; 35: 521-527.
Vimovo: (naproxen/esomeprazole magnesium) Delayed-released tablets, Pharmacy & Therapeutics, 2010, 35(9 Section 2): 2-4.
Vovk et al. "The modification of the pharmacokinetics and analgesic effect of naproxen by cimetidine, phenobarbital and thiamine diphosphate," Experiments in Clinical Pharmacology, 1996, vol. 59, Abstract only.

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US11324727B2 (en) 2020-07-15 2022-05-10 Schabar Research Associates, Llc Unit oral dose compositions composed of naproxen sodium and famotidine for the treatment of acute pain and the reduction of the severity of heartburn and/or the risk of heartburn
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US20170095455A1 (en) 2017-04-06
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US20180303801A1 (en) 2018-10-25

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